Technical Field
The present invention relates generally to biomedical compositions and methods for treating diseases, disorders and conditions affecting skin. In particular, the present invention provides compositions and methods for treating skin conditions that result from reactive oxygen species production in human skin, such as photoaging and other age-related skin damage, by highly effective delivery of antioxidants to skin fibroblasts and keratinocytes, including delivery to mitochondria in these cell types.
Description of the Related Art
In higher vertebrates including mammals and particularly in humans, skin is the largest body organ and serves as an important environmental interface, providing a protective envelope that is crucial for homeostasis. The outer layer of skin, the epidermis, is covered by the stratum corneum, a protective layer of dead epidermal skin cells (e.g., keratinocytes) and extracellular connective tissue proteins that is continually being sloughed off as it is replaced by new material pushed up from the underlying epidermal granular cell, spinous cell, and basal cell layers, where continuous cell division and protein synthesis produce new skin cells and skin proteins (e.g., keratin, collagen). Beneath the epidermis lies the dermis, in which dermal fibroblasts elaborate connective tissue proteins (e.g., collagen, elastin, etc.) that assemble into extracellular matrix and fibrous structures that give skin its flexibility, strength and elasticity. Nerves, blood vessels, smooth muscle cells, hair follicles and sebaceous glands are also present in the dermis.
Skin provides physicochemical protection against environmental insults through its barrier function, mechanical strength and imperviousness to water. Epidermal dendritic (Langerhans) cells, and migrating as well as resident white blood cells in the skin (e.g., lymphocytes, macrophages, mast cells) contribute to immunological protection while pigmented melanocytes in the basal layer absorb potentially harmful ultraviolet (UV) radiation.
Skin is also, however, a major target for toxic insult by a broad spectrum of physical (e.g., UV radiation) and chemical (e.g., xenobiotic) agents that are capable of altering its structure and function. Oxidative stress has been implicated as a major mediator of both natural skin aging and photoaging (accelerated skin aging due to UV exposure), which are typically accompanied by one or more undesirable effects such as wrinkling, dryness, itching, sagging, changes in texture, pigmentation or thickness, appearance of superficial blood vessels, appearance of growths including benign and precancerous lesions, and other sequelae. In natural aging including skin aging, oxidative stress derives from aerobic oxidative metabolism, which occurs in all human cells, and is required to maintain life. In skin photoaging, oxidative stress derives from photochemical conversion of electromagnetic energy into chemically reactive oxygen species (ROS) within skin cells exposed to solar UV irradiation. See, e.g., Mayachi, Skin Diseases Associated with Oxidative Injury, in Oxidative Stress in Dermatology, J. Fuchs (Ed.), Marcel Dekker, Inc., NY, 1993, pp. 323ff.
Oxidative stress sets in motion a complex array of cellular responses (e.g., Xu et al., 2006 Am. J. Pathol. 169:823; Xu et al., 2006 J. Biol. Chem. 281:27389). Among these responses is activation of signal transduction pathways that result in increased production of matrix metalloproteinases. Matrix metalloproteinases degrade the collagenous extracellular matrix that comprises skin connective tissue (dermis). Degradation of dermal extracellular matrix, which is composed primarily of type I collagen, impairs the structural integrity of the skin, and is largely responsible for the thin, wrinkled appearance of aged and photoaged skin. (Fisher et al., 2002 Arch. Dermatol. 138:1462).
Additionally, many environmental pollutants are either themselves oxidants, or else catalyze the production of reactive oxygen species (ROS) directly or indirectly. ROS are believed to activate cytoproliferative and/or cell survival signaling mechanisms, including mechanisms that can alter (e.g., up- or down-regulate in a statistically significant manner) apoptotic and other regulated pathways that may be involved in the pathogenesis of a number of skin disorders, including photosensitivity diseases and some types of cutaneous malignancy.
The skin possesses an array of defense mechanisms that interact with toxicants to obviate their deleterious effects. These protective mechanisms include non-enzymatic and enzymatic molecules that function as potent antioxidants or oxidant-degrading systems. Unfortunately, these homeostatic defenses, although highly effective, have limited capacity and can be overwhelmed, thereby leading to increased ROS in the skin that can foster the development of dermatological diseases.
A number of approaches to preventing or treating these ROS-mediated disorders in skin are based on the direct topical administration of various antioxidants in an effort to block oxidative damage of protein, DNA and phospholipids in tissues and cells, to restore physiological homeostasis (e.g., Farris, 2007 Dermatol. Ther. 20:322; Kang et al., 2003 J. Invest. Dermatol. 120:835; Kohen, 1999 Biomed. Pharmacother. 53:181). Such antioxidants include topical N-acetyl cysteine (e.g., Kang et al., 2003 J. Invest. Dermatol. 120:835), and other antioxidants typically based on the predominant form of human ubiquinone, Coenzyme Q10 (CoQ10). CoQ10, however, is a physiologically untargeted compound that generally exhibits poor bioavailability, at least in part due to its high degree of hydrophobicity, making it difficult to achieve protective levels of CoQ10 antioxidant activity at sites of oxidative damage.
Another untargeted antioxidant is the artificial ubiquinone, idebenone, a Coenzyme Q10 analogue. Idebenone has been shown to have antioxidant effects based on its ability to protect against cell damage from oxidative stress in a variety of biochemical, cell biological and in vivo methods (e.g., U.S. Pat. No. 6,756,045), including its ability as a topical agent to suppress sunburn cell formation in living skin (McDaniel et al., 2005 J. Cosmet. Dermatol. 4:10; see also review by Farris, 2007 Dermatol. Ther. 20:322). Idebenone has also been reported to protect skin from damage in a controlled clinical trial as a topical cream (McDaniel et al., 2005 J. Cosmet. Dermatol. 4:167), although its effectiveness as an antioxidant skin photoprotectant has been called into question (Tournas et al., 2006 J. Invest. Dermatol. 126:1185). Idebenone is available topically as a cosmetic (Prevage®) and is marketed by Allergan and Elizabeth Arden. As an untargeted antioxidant, however, idebenone lacks the ability to deliver high local concentrations of antioxidant activity to tissue, cellular and subcellular sites where oxidative damage may be occurring. For example, when tested on skin fibroblasts higher concentrations of idebenone than of CoQ10 were required to obtain significant cytoprotective effects, and neither compound was capable of accumulation in mitochondria, which are major sites for ROS generation (Jauslin et al., 2003 FASEB J. 17:1972). A large number of topical dermatologic products purport to protect skin against photoaging using antioxidants but generally provide only low concentrations of antioxidant compounds and exhibit poor absorption into the skin (Kang et al., 2003 J. Invest. Dermatol. 120:835; Tournas et al., 2006 J. Invest. Dermatol. 126:1185). Additionally, beneficial delivery, by untargeted antioxidants such as CoQ10 or idebenone, of antioxidant activity to other skin cell types remains to be demonstrated.
Multiple complex cellular respiratory, oxidative and metabolic processes are regulated in and by mitochondria, the principle cellular energy source in higher organisms. These processes include electron transport chain (ETC) activity, which drives oxidative phosphorylation to produce metabolic energy in the form of adenosine triphosphate (ATP), and which also underlies a central mitochondrial role in intracellular calcium homeostasis.
Highly reactive free radicals that have the potential for damaging cells and tissues may result from altered or defective mitochondrial activity, including but not limited to failure at any step of the ETC. These free radicals may include reactive oxygen species (ROS) such as superoxide, peroxynitrite and hydroxyl radicals, and potentially other reactive species that may be toxic to cells. For example, UV-induced signal transduction and ROS generation have been shown to induce matrix metalloproteinase (MMP) expression in human skin as part of a molecular mechanism underlying photoaging (Kang et al., 2003 J. Invest. Dermatol. 120:835).
Clearly there is a need in the art for improved compositions and methods for treating skin conditions that result from ROS generation and oxidative damage, including effective delivery of antioxidants to skin sites of ROS production such as keratinocyte and fibroblast mitochondria. The presently disclosed invention embodiments address this need and offer other related advantages.